Quality and turnaround times of viral load monitoring under prevention of mother-to-child transmission of HIV Option B+ in six South African districts with a high antenatal HIV burden

Background. Barriers to monitoring maternal HIV viral load (VL) and achieving 90% viral suppression during pregnancy and breastfeeding still need to be understood in South Africa (SA).Objectives. To measure quality of VL care and turnaround times (TATs) for returning VL results to women enrolled in the prevention of mother-to-child transmission of HIV (PMTCT) programme in primary healthcare facilities.Methods. Data were obtained from a 2018 cross-sectional evaluation of the PMTCT Option B+ programme in six SA districts with high antenatal and infant HIV prevalence. Quality of VL care was measured as the proportion of clients reporting that results were explained to them. TATs for VL results were calculated using dates abstracted from four to five randomly selected facility-based client records to report overall facility ‘short TAT’ (≥80% of records with TAT ≤7 days). Logistical regression and logit-based risk difference statistics were used.Results. Achieving overall short TAT was uncommon. Only 50% of facilities in one rural district, zero in one urban metro district and 9 - 38% in other districts had short TAT. The significant difference between districts was influenced by the duration of keeping results in facilities after receipt from the laboratory. Expected quality of VL care received ranged between 66% and 85%. Client-related factors significantly associated with low quality of care, observed in two urban districts and one rural district, included lower education, recent initiation of antiretroviral treatment and experiencing barriers to clinic visits. Experiencing clinic visit barriers was also negatively associated with short TATs.Conclusions. We demonstrate above-average quality of care and delayed return of results to PMTCT clients. Context-specific interventions are needed to shorten TATs

Beneficial HLA-mediated viral polymorphisms on the transmitted virus additively influence disease progression in HIV-1, subtype C infection

Transmitted viral factors have been shown to affect disease progression but whether infection with viruses carrying beneficial HLA-mediated escape polymorphisms affects disease progression in HLA-mismatched participants remains controversial

Closing the gaps to eliminate mother-to-child transmission of HIV (MTCT) in South Africa: Understanding MTCT case rates, factors that hinder the monitoring and attainment of targets, and potential game changers

Background. Ninety percent of the world’s HIV-positive pregnant women live in 22 countries. These 22 countries, including South Africa (SA) have prioritised the elimination of mother-to-child transmission of HIV (EMTCT). Since 2016 all 22 countries recommend lifelong antiretroviral treatment for all HIV-positive pregnant and lactating women. To measure South African national, provincial and district-level progress towards attaining EMTCT, we analysed the number of in utero (IU) paedatric HIV infections per 100 000 live births (IU case rate), and synthesised factors hindering the monitoring of EMTCT progress and attainment from the viewpoint of provincial and district-level healthcare managers and implementers. We highlight potential innovations to strengthen health systems and improve EMTCT programme delivery. Methods. We reviewed national-, provincial- and district-level birth HIV testing data from routine National Health Laboratory Services (NHLS) records between April 2016 and March 2017. To obtain a qualitative perspective from healthcare managers and implementers, we synthesised information from the nine 2016 provincial-level EMTCT stock-taking workshops. These workshops involve key provincial and district-level staff, mentors and supporting partners. Lastly, we highlight potential innovations presented at these workshops to overcome operational challenges. Results. The national IU mother-to-child transmission (MTCT) rate was 0.9%, which translated to an IU case rate of 245 HIV-positive neonates per 100 000 live births. Provincial IU percent MTCT risk ranged from 0.6% to 1.3%, with IU case rates ranging between 168 and 325 cases per 100 000 live births. District-level IU percent MTCT risk ranged from 0.4% to 1.9%. Potential game changers include: pre-conception counselling to optimise maternal-partner health, weekly dissemination of HIV polymerase chain reaction (PCR) and viral load reports from the NHLS to specific individuals who trace mothers and infants needing care, use of ward-based outreach teams and community caregivers to trace HIV-infected mothers and their infants to link them into care, inclusion of a unique identifier in patient-held infant Road to Health booklets to facilitate infant tracing and continuous quality improvement (CQI) processes within facilities and districts and implementation of an HIV-positive baby tool to understand the characteristics and risks of HIV-positive infants. On an ecological level, provinces and districts using community-based approaches and CQI methodology seemed to have lower MTCT and IU case rates. Conclusions. More quantitative analyses are needed to understand what proportion of the success can be attributed to community-based and CQI approaches and the impact of the potential game changers on progress towards EMTCT

Evidence of pervasive biologically functional secondary-structures within the genomes of eukaryotic single-stranded DNA viruses

Single-stranded DNA (ssDNA) viruses have genomes that are potentially capable of forming complex secondary-structures through Watson-Crick base-pairing between their constituent nucleotides. A few of the structural elements formed by such base-pairings are, in fact, known to have important functions during the replication of many ssDNA viruses. What is unknown, however, is (i) whether numerous additional ssDNA virus genomic structural elements predicted to exist by computational DNA folding methods actually exist, and (ii) whether those structures that do exist have any biological relevance. We therefore computationally inferred lists of the most evolutionarily conserved structures within a diverse selection of animal- and plant-infecting ssDNA viruses drawn from the families Circoviridae, Anelloviridae, Parvoviridae, Nanoviridae andGeminiviridae, and analysed these for evidence of natural selection favouring the maintenance of these structures. While we find evidence that is consistent with purifying selection being stronger at nucleotide sites that are predicted to be base-paired than it is at sites predicted to be unpaired, we also find strong associations between sites that are predicted to pair with one another and site pairs that are apparently coevolving in a complementary fashion. Collectively, these results indicate that natural selection actively preserves much of the pervasive secondary-structure that is evident within eukaryote-infecting ssDNA virus genomes and, therefore, that much of this structure is biologically functional. Lastly, we provide examples of various highly conserved but completely uncharacterised structural elements that likely have important functions within some of the ssDNA virus genomes analysed here

Closing the gaps to eliminate mother-to-child transmission of HIV (MTCT) in South Africa : understanding MTCT case rates, factors that hinder the monitoring and attainment of targets, and potential game changers

BACKGROUND. Ninety percent of the world’s HIV-positive pregnant women live in 22 countries. These 22 countries, including South Africa (SA) have prioritised the elimination of mother-to-child transmission of HIV (EMTCT). Since 2016 all 22 countries recommend lifelong antiretroviral treatment for all HIV-positive pregnant and lactating women. To measure South African national, provincial and district-level progress towards attaining EMTCT, we analysed the number of in utero (IU) paedatric HIV infections per 100 000 live births (IU case rate), and synthesised factors hindering the monitoring of EMTCT progress and attainment from the viewpoint of provincial and district-level healthcare managers and implementers. We highlight potential innovations to strengthen health systems and improve EMTCT programme delivery. METHODS. We reviewed national-, provincial- and district-level birth HIV testing data from routine National Health Laboratory Services (NHLS) records between April 2016 and March 2017. To obtain a qualitative perspective from healthcare managers and implementers, we synthesised information from the nine 2016 provincial-level EMTCT stock-taking workshops. These workshops involve key provincial and district-level staff, mentors and supporting partners. Lastly, we highlight potential innovations presented at these workshops to overcome operational challenges. RESULTS. The national IU mother-to-child transmission (MTCT) rate was 0.9%, which translated to an IU case rate of 245 HIV-positive neonates per 100 000 live births. Provincial IU percent MTCT risk ranged from 0.6% to 1.3%, with IU case rates ranging between 168 and 325 cases per 100 000 live births. District-level IU percent MTCT risk ranged from 0.4% to 1.9%. Potential game changers include: pre-conception counselling to optimise maternal-partner health, weekly dissemination of HIV polymerase chain reaction (PCR) and viral load reports from the NHLS to specific individuals who trace mothers and infants needing care, use of ward-based outreach teams and community caregivers to trace HIV-infected mothers and their infants to link them into care, inclusion of a unique identifier in patient-held infant Road to Health booklets to facilitate infant tracing and continuous quality improvement (CQI) processes within facilities and districts and implementation of an HIV-positive baby tool to understand the characteristics and risks of HIV-positive infants. On an ecological level, provinces and districts using community-based approaches and CQI methodology seemed to have lower MTCT and IU case rates. CONCLUSIONS. More quantitative analyses are needed to understand what proportion of the success can be attributed to community-based and CQI approaches and the impact of the potential game changers on progress towards EMTCT.The South African Medical Research Council paid for the time of AG, WC and NN, and, in partnership with UNICEF, covered the cost of this publication.http://www.samj.org.zaam2019Paediatrics and Child Healt

Evidence of HIV-1 adaptation to host HLA alleles following chimp-to-human transmission

<p>Abstract</p> <p>Background</p> <p>The cytotoxic T-lymphocyte immune response is important in controlling HIV-1 replication in infected humans. In this immune pathway, viral peptides within infected cells are presented to T-lymphocytes by the polymorphic human leukocyte antigens (HLA). HLA alleles exert selective pressure on the peptide regions and immune escape mutations that occur at some of the targeted sites can enable the virus to adapt to the infected host. The pattern of ongoing immune escape and reversion associated with several human HLA alleles has been studied extensively. Such mutations revert upon transmission to a host without the HLA allele because the escape mutation incurs a fitness cost. However, to-date there has been little attempt to study permanent loss of CTL epitopes due to escape mutations without an effect on fitness.</p> <p>Results</p> <p>Here, we set out to determine the extent of adaptation of HIV-1 to three well-characterized HLA alleles during the initial exposure of the virus to the human cytotoxic immune responses following transmission from chimpanzee. We generated a chimpanzee consensus sequence to approximate the virus sequence that was initially transmitted to the human host and used a method based on peptide binding affinity to HLA crystal structures to predict peptides that were potentially targeted by the HLA alleles on this sequence. Next, we used codon-based phylogenetic models to quantify the average selective pressure that acted on these regions during the period immediately following the zoonosis event, corresponding to the branch of the phylogenetic tree leading to the common ancestor of all of the HIV-1 sequences. Evidence for adaptive evolution during this period was observed at regions recognised by HLA A*6801 and A*0201, both of which are common in African populations. No evidence of adaptive evolution was observed at sites targeted by HLA-B*2705, which is a rare allele in African populations.</p> <p>Conclusion</p> <p>Our results suggest that the ancestral HIV-1 virus experienced a period of positive selective pressure due to immune responses associated with HLA alleles that were common in the infected human population. We propose that this resulted in permanent escape from immune responses targeting unconstrained regions of the virus.</p

The Unknown Risk of Vertical Transmission in Sleeping Sickness—A Literature Review

Children with human African trypanosomiasis (HAT) present with a range of generally non-specific symptoms. Late diagnosis is frequent with often tragic outcomes. Trypanosomes can infect the foetus by crossing the placenta. Unequivocal cases of congenital infection that have been reported include newborn babies of infected mothers who were diagnosed with HAT in the first 5 days of life and children of infected mothers who had never entered an endemic country themselves

Modeling HIV-1 Drug Resistance as Episodic Directional Selection

The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance

The effects of an extensive exercise programme on the progression of Mild Cognitive Impairment (MCI): study protocol for a randomised controlled trial

Background Exercise interventions to prevent dementia and delay cognitive decline have gained considerable attention in recent years. Human and animal studies have demonstrated that regular physical activity targets brain function by increasing cognitive reserve. There is also evidence of structural changes caused by exercise in preventing or delaying the genesis of neurodegeneration. Although initial studies indicate enhanced cognitive performance in patients with mild cognitive impairment (MCI) following an exercise intervention, little is known about the effect of an extensive, controlled and regular exercise regimen on the neuropathology of patients with MCI. This study aims to determine the effects of an extensive exercise programme on the progression of MCI. Methods/design This randomised controlled clinical intervention study will take place across three European sites. Seventy-five previously sedentary patients with a clinical diagnosis of MCI will be recruited at each site. Participants will be randomised to one of three groups. One group will receive a standardised 1-year extensive aerobic exercise intervention (3 units of 45 min/week). The second group will complete stretching and toning (non-aerobic) exercise (3 units of 45 min/week) and the third group will act as the control group. Change in all outcomes will be measured at baseline (T0), after six months (T1) and after 12 months (T2). The primary outcome, cognitive performance, will be determined by a neuropsychological test battery (CogState battery, Trail Making Test and Verbal fluency). Secondary outcomes include Montreal Cognitive Assessment (MoCA), cardiovascular fitness, physical activity, structural changes of the brain, quality of life measures and measures of frailty. Furthermore, outcome variables will be related to genetic variations on genes related to neurogenesis and epigenetic changes in these genes caused by the exercise intervention programme. Discussion The results will add new insights into the prevailing notion that exercise may slow the rate of cognitive decline in MCI